Citations

Mutations in the electrogenic Na+/ nHCO3− cotransporter (NBCe1, SLC4A4) cause severe proximal renal tubular acidosis, glaucoma, and cataracts in humans, indicating NBCe1 has a critical role in acid-base homeostasis and ocular fluid transport. To better understand the homeostatic roles and protein ontogeny of NBCe1, we have cloned, localized, and downregulated NBCe1 expression in zebrafish, and examined its transport characteristics when expressed in Xenopus oocytes. Zebrafish NBCe1 (zNBCe1) is 80% identical to published mammalian NBCe1 cDNAs. Like other fish NBCe1 clones, zebrafish NBCe1 is most similar to the pancreatic form of mammalian NBC (Slc4a4-B) but appears to be the dominant isoform found in zebrafish. In situ hybridization of embryos demonstrated mRNA expression in kidney pronephros and eye by 24 h postfertilization (hpf) and gill and brain by 120 hpf. Immunohistochemical labeling demonstrated expression in adult zebrafish eye and gill. Morpholino knockdown studies demonstrated roles in eye and brain development and caused edema, indicating altered fluid and electrolyte balance. With the use of microelectrodes to measure membrane potential ( Vm), voltage clamp (VC), intracellular pH (pHi), or intracellular Na+ activity ( aNai), we examined the function of zNBCe1 expressed in Xenopus oocytes. Zebrafish NBCe1 shared transport properties with mammalian NBCe1s, demonstrating electrogenic Na+ and HCO3− transport as well as similar drug sensitivity, including inhibition by 4,4′-diiso-thiocyano-2,2′-disulfonic acid stilbene and tenidap. These data indicate that NBCe1 in zebrafish shares many characteristics with mammalian NBCe1, including tissue distribution, importance in systemic water and electrolyte balance, and electrogenic transport of Na+ and HCO3−. Thus zebrafish promise to be useful model system for studies of NBCe1 physiology.

Abstract Inherited BRCA1/2 mutations confer elevated ovarian cancer risk. Knowledge of factors that can improve ovarian cancer risk assessment in BRCA1/2 mutation carriers is important because no effective early detection for ovarian cancers exists. A cohort of 1,575 BRCA1 and 856 BRCA2 mutation carriers was used to evaluate haplotypes at ATM, BARD1, BRIP1, CTIP, MRE11, NBS1, RAD50, RAD51, and TOPBP1 in ovarian cancer risk. In BRCA1 carriers, no associations were observed with ATM, BARD1, CTIP, RAD50, RAD51, or TOPBP1. At BRIP1, an association was observed for one haplotype with a multiple testing corrected P (Pcorr) = 0.012, although no individual haplotype was significant. At MRE11, statistically significant associations were observed for one haplotype (Pcorr = 0.007). At NBS1, we observed a Pcorr = 0.024 for haplotypes. In BRCA2 carriers, no associations were observed with CTIP, NBS1, RAD50, or TOPBP1. Rare haplotypes at ATM (Pcorr = 0.044) and BARD1 (Pcorr = 0.012) were associated with ovarian cancer risk. At BRIP1, two common haplotypes were significantly associated with ovarian cancer risk (Pcorr = 0.011). At MRE11, we observed a significant haplotype association (Pcorr = 0.012), and at RAD51, one common haplotype was significantly associated with ovarian cancer risk (Pcorr = 0.026). Variants in genes that interact biologically withBRCA1 and/or BRCA2 may be associated with modified ovarian cancer risk in women who carry BRCA1/2 mutations. [Cancer Res 2009;69(14):5801–10]

Background and Purpose— Embolic events have long been thought to occur in patients with cardiac tumors secondary to embolization of tumor fragments; however, there are no large studies examining the epidemiology and occurrence of embolism in this group of patients. Methods— From 1957 to 2006, 323 consecutive patients with primary cardiac tumors were treated surgically at our institution. Of these, patients who experienced an embolic event included 80 (cerebrovascular accident 31 [9.7%], transient ischemic attack 30 [9.3%], and other 19 [6%]). Those with no history of an embolic event (n=243 [75%]) were defined as control subjects. Results— Age was similar between the case and control groups (mean 54.5 versus 53.9 years, P =0.8). A multivariate logistic regression model including tumor location, tumor burden, tumor histology, and cerebrovascular risk factors, indicated that left atrial tumors (OR, 1.95; P =0.04), aortic valve tumors (OR, 4.17; P =0.002), and smaller tumor burden (OR, 2.20; P =0.01) were the most significant factors in the occurrence of embolism ( P <0.001). The presence of mitral regurgitation (OR, 0.12; P =0.006) and decreased functional status (New York Heart Association III/IV; OR, 0.31; P <0.001) were protective against the occurrence of embolism. Follow-up was obtained in 82% at a mean follow-up time of 6.17±6.9 years. There were no recurrent embolic events at follow-up. A Kaplan-Meier survival curve demonstrated no difference in survival between both groups ( P =0.78). Conclusion— Aortic valve and left atrial tumors have the greatest anatomic risk for embolism. Furthermore, patients with smaller tumors, minimal symptomatology, and no evidence of mitral regurgitation have a high risk of embolism. Cardiac tumors can be resected with low early mortality, and late survival after operation in the context of an embolic event is similar to patients with cardiac tumors who undergo resection for other indications.

Background— Primary cardiac tumors are rare but have the potential to cause significant morbidity if not treated in an appropriate and timely manner. To date, however, there have been no studies examining survival characteristics of patients who undergo surgical resection. Methods and Results— From 1957 to 2006, 323 consecutive patients underwent surgical resection of primary cardiac tumors; 163 (50%) with myxomas, 83 (26%) with papillary fibroelastomas, 18 (6%) with fibromas, 12 (4%) with lipomas, 28 (9%) with other benign primary cardiac tumors, and 19 (6%) with primary malignant tumors. Operative (30 day) mortality was 2% (n=6). Univariate analysis indicated that patients who underwent resection of fibromas and myxomas had superior survival characteristics in comparison to the remainder of tumor variants; these results were consistent after adjusting for age at surgery, year of surgery, and cardiovascular risk factors. Based on actuarial characteristics of the 2002 U.S. population, patients who underwent myxoma resection had survival characteristics that were not significantly different from that of an age and gender matched population (SMR 1.11, P =0.57) whereas those who underwent resection of fibromas (SMR 11.17, P =0.002), papillary fibroelastomas (SMR 3.17, P =0.0003), lipomas (SMR 5.0, P =0.0003), other benign tumors (SMR 4.63, P =0.003), and malignant tumors (SMR 101, P <0.0001) had significantly poorer survival characteristics. Furthermore, malignant tumors in younger patients were highly fatal (HR 0.899, P <0.0001). Although the most significant predictor of mortality was tumor histology, survival was also influenced the by the duration of CPB and NYHA III/IV; the impact of these risk factors varied with time. The cumulative incidence of myxoma recurrence was 13% and occurred in a younger population (42 versus 57 years, P =0.003) with the risk of recurrence decreased after 4 years. Conclusions— Surgical resection of primary cardiac tumors is associated with excellent long-term survival; patients with cardiac myxomas have survival characteristics that are not significantly different from that of a general population. Predictors of mortality are primarily related to tumor histology but also include clinical characteristics such as symptomatology and duration of CPB.

AbstractThe AURKA oncogene is associated with abnormal chromosome segregation and aneuploidy and predisposition to cancer. Amplification of AURKA has been detected at higher frequency in tumors from BRCA1 and BRCA2 mutation carriers than in sporadic breast tumors, suggesting that overexpression of AURKA and inactivation of BRCA1 and BRCA2 cooperate during tumor development and progression. The F31I polymorphism in AURKA has been associated with breast cancer risk in the homozygous state in prior studies. We evaluated whether the AURKA F31I polymorphism modifies breast cancer risk in BRCA1 and BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2. Consortium of Investigators of Modifiers of BRCA1/2 was established to provide sufficient statistical power through increased numbers of mutation carriers to identify polymorphisms that act as modifiers of cancer risk and can refine breast cancer risk estimates in BRCA1 and BRCA2 mutation carriers. A total of 4,935 BRCA1 and 2,241 BRCA2 mutation carriers and 11 individuals carrying both BRCA1 and BRCA2 mutations was genotyped for F31I. Overall, homozygosity for the 31I allele was not significantly associated with breast cancer risk in BRCA1 and BRCA2 carriers combined [hazard ratio (HR), 0.91; 95% confidence interval (95% CI), 0.77-1.06]. Similarly, no significant association was seen in BRCA1 (HR, 0.90; 95% CI, 0.75-1.08) or BRCA2 carriers (HR, 0.93; 95% CI, 0.67-1.29) or when assessing the modifying effects of either bilateral prophylactic oophorectomy or menopausal status of BRCA1 and BRCA2 carriers. In summary, the F31I polymorphism in AURKA is not associated with a modified risk of breast cancer in BRCA1 and BRCA2 carriers. (Cancer Epidemiol Biomarkers Prev 2007;16(7):1416–21)

Background—There are few data regarding medium-term outcome of coronary artery bypass grafting (CABG) in patients with severe left ventricular (LV) systolic dysfunction, particularly in the modern era, and even less assessing preoperative factors that might identify patients at highest risk.Methods and Results—Three hundred seventy-nine consecutive patients with LV ejection fraction ≤35%, who underwent isolated first CABG between 1995 and 1999 were studied. Potential preoperative and perioperative predictors of outcome were recorded and patients followed-up for a median of 3.8 years. The primary study end-point was all-cause mortality. The 30-day, 1-year, and 3-year survival rates were 94.5%, 88%, and 81%, respectively. The independent predictors of mortality were preoperative estimated glomerular filtration rate (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.97 to 0.99 per mL/min/1.73m2;P<0.001) and age (HR, 1.03; 95% CI, 1.01 to 1.06 per year;P=0.005).Conclusions—Patients with significant LV systolic dysfunction undergoing isolated CABG using contemporary techniques have a good medium-term survival. Renal dysfunction is the strongest independent predictor of mortality.

Background— This study evaluated long-term results of aortic root replacement and valve-preserving aortic root reconstruction for patients with aneurysms involving the aortic root. Methods and Results— Two-hundred three patients aged 53±16 years (mean±SD; 153 male, 50 female) underwent elective or urgent aortic root surgery from 1971 to 2000 for an aortic root aneurysm: 149 patients underwent a composite valve conduit reconstruction, and 54 patients underwent valve-preserving aortic root reconstruction. Fifty patients had Marfan syndrome. In-hospital and 30-day mortality was 4.0% (8/203) overall: for a composite valve conduit procedure, the corresponding value was 4.0% (6/149) and for valve-preserving procedure, 3.7% (2/54) ( P =NS). Morbidity included 3 strokes (1%), 10 perioperative myocardial infarctions (5%), and 8 reoperations for bleeding (4%). Actuarial survival at 5, 10, 15, and 20 years was 93% (95% confidence interval [CI] = 88% to 97%), 79% (95% CI = 71% to 87%), 67% (95% CI = 57% to 79%), and 52% (95% CI = 36% to 69%), respectively. Freedom from reoperation was 72% (95% CI = 54% to 86%) at 20 years. Complications with anticoagulation occurred in 29 patients; with valve thrombosis, in 2; and with hemorrhage, in 27 (4 life threatening and 23 minor). Freedom from thromboembolism was 91% (95% CI = 77% to 98%) at 20 years. Freedom from endocarditis was 99% (95% CI = 92% to 100%) at 20 years. Multivariate analysis revealed preoperative mitral valve regurgitation (+3 to 4) and older age to be significant predictors of late death ( P ≤0.005), and Marfan syndrome, initial valve-preserving aortic root reconstruction, and need for a concomitant procedure at initial operation to be significant predictors of the need for reoperation ( P ≤0.01). Conclusions— Aortic root replacement for aortic root aneurysms can be done with low morbidity and mortality. Composite valve conduit reconstruction resulted in a durable result. There were few serious complications related to the need for long-term anticoagulation or a prosthetic valve. Reoperation was most commonly required because of failure of the aortic valve when a valve-preserving aortic root reconstruction was performed or for other cardiac or aortic disease elsewhere.